Molecular Imaging and Biology

, Volume 20, Issue 4, pp 667–681 | Cite as

[11C]Harmine Binding to Brain Monoamine Oxidase A: Test-Retest Properties and Noninvasive Quantification

  • Francesca ZanderigoEmail author
  • Alexandra E. D’Agostino
  • Nandita Joshi
  • Martin Schain
  • Dileep Kumar
  • Ramin V. Parsey
  • Christine DeLorenzo
  • J. John Mann
Research Article



Inhibition of the isoform A of monoamine oxidase (MAO-A), a mitochondrial enzyme catalyzing deamination of monoamine neurotransmitters, is useful in treatment of depression and anxiety disorders. [11C]harmine, a MAO-A PET radioligand, has been used to study mood disorders and antidepressant treatment. However, [11C]harmine binding test-retest characteristics have to date only been partially investigated. Furthermore, since MAO-A is ubiquitously expressed, no reference region is available, thus requiring arterial blood sampling during PET scanning. Here, we investigate [11C]harmine binding measurements test-retest properties; assess effects of using a minimally invasive input function estimation on binding quantification and repeatability; and explore binding potentials estimation using a reference region-free approach.


Quantification of [11C]harmine distribution volume (VT) via kinetic models and graphical analyses was compared based on absolute test-retest percent difference (TRPD), intraclass correlation coefficient (ICC), and identifiability. The optimal procedure was also used with a simultaneously estimated input function in place of the measured curve. Lastly, an approach for binding potentials quantification in absence of a reference region was evaluated.


[11C]harmine VT estimates quantified using arterial blood and kinetic modeling showed average absolute TRPD values of 7.7 to 15.6 %, and ICC values between 0.56 and 0.86, across brain regions. Using simultaneous estimation (SIME) of input function resulted in VT estimates close to those obtained using arterial input function (r = 0.951, slope = 1.073, intercept = − 1.037), with numerically but not statistically higher test-retest difference (range 16.6 to 22.0 %), but with overall poor ICC values, between 0.30 and 0.57.


Prospective studies using [11C]harmine are possible given its test-retest repeatability when binding is quantified using arterial blood. Results with SIME of input function show potential for simplifying data acquisition by replacing arterial catheterization with one arterial blood sample at 20 min post-injection. Estimation of [11C]harmine binding potentials remains a challenge that warrants further investigation.

Key words

Positron emission tomography Brain Monoamine oxidase A Repeatability Noninvasive estimation 



The authors would like to thank Dr. Rajan Murthy for his help with the protocol used to acquire the scans.

Funding Information

This research was supported by 5P50MH062185, Conte Center: The Neurobiology of Suicidal Behavior (National Institute for Mental Health) (PI: Mann).

Compliance with Ethical Standards

Conflicts of Interest

Drs. Zanderigo, D’Agostino, Schain, Kumar, Parsey, and Delorenzo, and Ms. Joshi declare no conflicts of interest. Dr. Mann receives royalties for commercial use of the Columbia-Suicide Severity Rating Scales from the Research Foundation for Mental Hygiene.

Supplementary material

11307_2018_1165_MOESM1_ESM.pdf (573 kb)
ESM 1 (PDF 573 kb)


  1. 1.
    Weyler W, Hsu YP, Breakefield XO (1990) Biochemistry and genetics of monoamine oxidase. Pharmacol Ther 47(3):391–417. CrossRefPubMedGoogle Scholar
  2. 2.
    Johnston JP (1968) Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 17(7):1285–1297. CrossRefPubMedGoogle Scholar
  3. 3.
    Shih JC, Chen K, Ridd MJ (1999) Monoamine oxidase: from genes to behavior. Annu Rev Neurosci 22(1):197–217. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Youdim MB, Edmondson D, Tipton KF (2006) The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 7(4):295–309. CrossRefPubMedGoogle Scholar
  5. 5.
    Livingston MG, Livingston HM (1996) Monoamine oxidase inhibitors. An update on drug interactions. Drug Saf 14(4):219–227. CrossRefPubMedGoogle Scholar
  6. 6.
    Meyer JH, Ginovart N, Boovariwala A, Sagrati S, Hussey D, Garcia A, Young T, Praschak-Rieder N, Wilson AA, Houle S (2006) Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry 63(11):1209–1216. CrossRefPubMedGoogle Scholar
  7. 7.
    Ametamey SM, Beer HF, Guenther I, Antonini A, Leenders KL, Waldmeier PC, Schubiger PA (1996) Radiosynthesis of [11C]brofaromine, a potential tracer for imaging monoamine oxidase a. Nucl Med Biol 23(3):229–234. CrossRefPubMedGoogle Scholar
  8. 8.
    Bottlaender M, Dolle F, Guenther I, Roumenov D, Fuseau C, Bramoulle Y, Curet O, Jegham J, Pinquier JL, George P, Valette H (2003) Mapping the cerebral monoamine oxidase type A: positron emission tomography characterization of the reversible selective inhibitor [11C]befloxatone. J Pharmacol Exp Ther 305(2):467–473. CrossRefPubMedGoogle Scholar
  9. 9.
    Fowler JS, MacGregor RR, Wolf AP et al (1987) Mapping human brain monoamine oxidase A and B with 11C-labeled suicide inactivators and PET. Science 235(4787):481–485. CrossRefPubMedGoogle Scholar
  10. 10.
    Ohmomo Y, Hirata M, Murakami K et al (1991) Synthesis of fluorine and iodine analogues of clorgyline and selective inhibition of monoamine oxidase A. Chem Pharm Bull (Tokyo) 39(4):1038–1040. CrossRefGoogle Scholar
  11. 11.
    Ohmomo Y, Hirata M, Murakami K et al (1993) Synthesis and characterization of 11C-labeled fluoroclorgyline: a monoamine oxidase A specific inhibitor for positron emission tomography. Chem Pharm Bull (Tokyo) 41(11):1994–1997. CrossRefGoogle Scholar
  12. 12.
    Bergstrom M, Westerberg G, Kihlberg T, Langstrom B (1997) Synthesis of some 11C-labelled MAO-A inhibitors and their in vivo uptake kinetics in rhesus monkey brain. Nucl Med Biol 24(5):381–388. CrossRefPubMedGoogle Scholar
  13. 13.
    Bergstrom M, Westerberg G, Langstrom B (1997) 11C-harmine as a tracer for monoamine oxidase A (MAO-A): in vitro and in vivo studies. Nucl Med Biol 24(4):287–293. CrossRefPubMedGoogle Scholar
  14. 14.
    Kim H, Sablin SO, Ramsay RR (1997) Inhibition of monoamine oxidase A by beta-carboline derivatives. Arch Biochem Biophys 337(1):137–142. CrossRefPubMedGoogle Scholar
  15. 15.
    Murthy R, Erlandsson K, Kumar D, van Heertum R, Mann J, Parsey R (2007) Biodistribution and radiation dosimetry of 11Charmine in baboons. Nucl Med Commun 28(9):748–754. CrossRefPubMedGoogle Scholar
  16. 16.
    Chiuccariello L, Houle S, Miler L, Cooke RG, Rusjan PM, Rajkowska G, Levitan RD, Kish SJ, Kolla NJ, Ou X, Wilson AA, Meyer JH (2014) Elevated monoamine oxidase a binding during major depressive episodes is associated with greater severity and reversed neurovegetative symptoms. Neuropsychopharmacology 39(4):973–980. CrossRefPubMedGoogle Scholar
  17. 17.
    Meyer JH, Wilson AA, Sagrati S, Miler L, Rusjan P, Bloomfield PM, Clark M, Sacher J, Voineskos AN, Houle S (2009) Brain monoamine oxidase A binding in major depressive disorder: relationship to selective serotonin reuptake inhibitor treatment, recovery, and recurrence. Arch Gen Psych 66(12):1304–1312. CrossRefGoogle Scholar
  18. 18.
    Sacher J, Houle S, Parkes J, Rusjan P, Sagrati S, Wilson AA, Meyer JH (2011) Monoamine oxidase A inhibitor occupancy during treatment of major depressive episodes with moclobemide or St. John’s wort: an [11C]-harmine PET study. J Psychiatry Neurosci 36(6):375–382. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Sacher J, Wilson AA, Houle S, Rusjan P, Hassan S, Bloomfield PM, Stewart d, Meyer JH (2010) Elevated brain monoamine oxidase A binding in the early postpartum period. Arch Gen Psych 67(5):468–474. CrossRefGoogle Scholar
  20. 20.
    Sacher J, Rabiner EA, Clark M, Rusjan P, Soliman A, Boskovic R, Kish SJ, Wilson AA, Houle S, Meyer JH (2012) Dynamic, adaptive changes in MAO-A binding after alterations in substrate availability: an in vivo [11C]-harmine positron emission tomography study. J Cereb Blood Flow Metabolism 32(3):443–446. CrossRefGoogle Scholar
  21. 21.
    Kolla NJ, Matthews B, Wilson AA, Houle S, Michael Bagby R, Links P, Simpson AI, Hussain A, Meyer JH (2015) Lower monoamine oxidase-A total distribution volume in impulsive and violent male offenders with antisocial personality disorder and high psychopathic traits: an [11C] Harmine positron emission tomography study. Neuropsychopharmacology 40(11):2596–2603. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kolla NJ, Chiuccariello L, Wilson AA, Houle S, Links P, Bagby RM, McMain S, Kellow C, Patel J, Rekkas PV, Pasricha S, Meyer JH (2016) Elevated monoamine oxidase-a distribution volume in borderline personality disorder is associated with severity across mood symptoms, suicidality, and cognition. Biol Psych 79(2):117–126. CrossRefGoogle Scholar
  23. 23.
    Ginovart N, Meyer JH, Boovariwala A, Hussey D, Rabiner EA, Houle S, Wilson AA (2006) Positron emission tomography quantification of [11C]-harmine binding to monoamine oxidase-A in the human brain. J Cereb Blood Flow Metabolism 26(3):330–344. CrossRefGoogle Scholar
  24. 24.
    Gunn RN, Gunn SR, Cunningham VJ (2001) Positron emission tomography compartmental models. J Cereb Blood Flow Metab 21(6):635–652. CrossRefPubMedGoogle Scholar
  25. 25.
    Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, MacGregor RR, Hitzemann R, Bendriem B, Gatley SJ, Christman DR (1990) Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 10(5):740–747. CrossRefPubMedGoogle Scholar
  26. 26.
    Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, Holden J, Houle S, Huang SC, Ichise M, Iida H, Ito H, Kimura Y, Koeppe RA, Knudsen GM, Knuuti J, Lammertsma AA, Laruelle M, Logan J, Maguire RP, Mintun MA, Morris ED, Parsey R, Price JC, Slifstein M, Sossi V, Suhara T, Votaw JR, Wong DF, Carson RE (2007) Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 27(9):1533–1539. CrossRefPubMedGoogle Scholar
  27. 27.
    Saura J, Kettler R, Da Prada M, Richards JG (1992) Quantitative enzyme radioautography with 3H-Ro 41-1049 and 3H-Ro 19-6327 in vitro: localization and abundance of MAO-A and MAO-B in rat CNS, peripheral organs, and human brain. J Neurosci 12(5):1977–1999CrossRefPubMedGoogle Scholar
  28. 28.
    Saura J, Bleuel Z, Ulrich J, Mendelowitsch A, Chen K, Shih JC, Malherbe P, da Prada M, Richards JG (1996) Molecular neuroanatomy of human monoamine oxidases a and B revealed by quantitative enzyme radioautography and in situ hybridization histochemistry. Neuroscience 70(3):755–774. CrossRefPubMedGoogle Scholar
  29. 29.
    Todd Ogden R, Zanderigo F, Parsey RV (2015) Estimation of in vivo nonspecific binding in positron emission tomography studies without requiring a reference region. NeuroImage 108:234–242. CrossRefPubMedGoogle Scholar
  30. 30.
    First MB, Spitzer RL, Gibbon M, Williams JB (2012) Structured Clinical Interview for DSM-IV® Axis I Disorders (SCID-I), Clinician Version, : American Psychiatric PubGoogle Scholar
  31. 31.
    Avants BB, Tustison NJ, Wu J, Cook PA, Gee JC (2011) An open source multivariate framework for n-tissue segmentation with evaluation on public data. Neuroinformatics 9(4):381–400. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Milak MS, DeLorenzo C, Zanderigo F, Prabhakaran J, Kumar JSD, Majo VJ, Mann JJ, Parsey RV (2010) In vivo quantification of human serotonin 1A receptor using 11C-CUMI-101, an agonist PET radiotracer. J Nucl Med 51(12):1892–1900. CrossRefPubMedGoogle Scholar
  33. 33.
    Shattuck DW, Mirza M, Adisetiyo V, Hojatkashani C, Salamon G, Narr KL, Poldrack RA, Bilder RM, Toga AW (2008) Construction of a 3D probabilistic atlas of human cortical structures. NeuroImage 39(3):1064–1080. CrossRefPubMedGoogle Scholar
  34. 34.
    Gunn RN, Sargent PA, Bench CJ, Rabiner EA, Osman S, Pike VW, Hume SP, Grasby PM, Lammertsma AA (1998) Tracer kinetic modeling of the 5-HT1A receptor ligand [carbonyl-11C]WAY-100635 for PET. NeuroImage 8(4):426–440. CrossRefPubMedGoogle Scholar
  35. 35.
    Parsey RV, Ojha A, Ogden RT, Erlandsson K, Kumar D, Landgrebe M, van Heertum R, Mann JJ (2006) Metabolite considerations in the in vivo quantification of serotonin transporters using 11C-DASB and PET in humans. J Nucl Med 47(11):1796–1802PubMedGoogle Scholar
  36. 36.
    Parsey RV, Slifstein M, Hwang DR, Abi-Dargham A, Simpson N, Mawlawi O, Guo NN, van Heertum R, Mann JJ, Laruelle M (2000) Validation and reproducibility of measurement of 5-HT1A receptor parameters with [carbonyl-11C]WAY-100635 in humans: comparison of arterial and reference tissue input functions. J Cereb Blood Flow Metab 20(7):1111–1133. CrossRefPubMedGoogle Scholar
  37. 37.
    Watson CC, Newport D, Casey ME (1996) A single scatter simulation technique for scatter correction in 3D PET. In: Grangeat P, Amans JL (eds) Three-dimensional image reconstruction in radiology and nuclear medicine. Computational imaging and vision, vol 4. Springer, Dordrecht. CrossRefGoogle Scholar
  38. 38.
    Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang DR, Huang Y, Simpson N, Ngo K, van Heertum R, Laruelle M (2001) Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab 21(9):1034–1057. CrossRefPubMedGoogle Scholar
  39. 39.
    Slifstein M, Laruelle M (2001) Models and methods for derivation of in vivo neuroreceptor parameters with PET and SPECT reversible radiotracers. Nucl Med Biol 28(5):595–608. CrossRefPubMedGoogle Scholar
  40. 40.
    Ogden RT (2003) Estimation of kinetic parameters in graphical analysis of PET imaging data. Statistics Med 22(22):3557–3568. CrossRefGoogle Scholar
  41. 41.
    Akaike H (1974) A new look at the statistical model identification. IEEE Trans Automat Contr AC-19(6):716–23.
  42. 42.
    Rosario BL, Weissfeld LA, Laymon CM, Mathis CA, Klunk WE, Berginc MD, James JA, Hoge JA, Price JC (2011) Inter-rater reliability of manual and automated region-of-interest delineation for PiB PET. NeuroImage 55(3):933–941. CrossRefPubMedGoogle Scholar
  43. 43.
    Ogden RT, Tarpey T (2006) Estimation in regression models with externally estimated parameters. Biostatistics 7(1):115–129. CrossRefPubMedGoogle Scholar
  44. 44.
    Ogden RT, Ojha A, Erlandsson K, Oquendo MA, Mann JJ, Parsey RV (2007) In vivo quantification of serotonin transporters using [11C]DASB and positron emission tomography in humans: modeling considerations. J Cereb Blood Flow Metab 27(1):205–217. CrossRefPubMedGoogle Scholar
  45. 45.
    Ogden RT, Zanderigo F, Choy S, Mann JJ, Parsey RV (2010) Simultaneous estimation of input functions: an empirical study. J Cereb Blood Flow Metab 30(4):816–826. CrossRefPubMedGoogle Scholar
  46. 46.
    Collste K, Forsberg A, Varrone A, Amini N, Aeinehband S, Yakushev I, Halldin C, Farde L, Cervenka S (2016) Test-retest reproducibility of [11C]PBR28 binding to TSPO in healthy control subjects. Eur J Nucl Med Mol Imaging 43(1):173–183. CrossRefPubMedGoogle Scholar
  47. 47.
    Naganawa M, Zheng MQ, Henry S, Nabulsi N, Lin SF, Ropchan J, Labaree D, Najafzadeh S, Kapinos M, Tauscher J, Neumeister A, Carson RE, Huang Y (2015) Test-retest reproducibility of binding parameters in humans with 11C-LY2795050, an antagonist PET radiotracer for the kappa opioid receptor. J Nucl Med 56(2):243–248. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Bacher I, Houle S, Xu X, Zawertailo L, Soliman A, Wilson AA, Selby P, George TP, Sacher J, Miler L, Kish SJ, Rusjan P, Meyer JH (2011) Monoamine oxidase A binding in the prefrontal and anterior cingulate cortices during acute withdrawal from heavy cigarette smoking. Arch Gen Psych 68(8):817–826. CrossRefGoogle Scholar
  49. 49.
    Soliman A, Bagby RM, Wilson AA, Miler L, Clark M, Rusjan P, Sacher J, Houle S, Meyer JH (2011) Relationship of monoamine oxidase A binding to adaptive and maladaptive personality traits. Psychol Med 41(05):1051–1060. CrossRefPubMedGoogle Scholar
  50. 50.
    Slifstein M, Laruelle M (2000) Effects of statistical noise on graphic analysis of PET neuroreceptor studies. J Nucl Med 41(12):2083–2088PubMedGoogle Scholar
  51. 51.
    Barth C, Villringer A, Sacher J (2015) Sex hormones affect neurotransmitters and shape the adult female brain during hormonal transition periods. Front Neurosci 9:37CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Gundlah C, Lu NZ, Bethea CL (2002) Ovarian steroid regulation of monoamine oxidase-A and -B mRNAs in the macaque dorsal raphe and hypothalamic nuclei. Psychopharmacology 160(3):271–282. CrossRefPubMedGoogle Scholar
  53. 53.
    Rekkas PV, Wilson AA, Lee VW et al (2014) Greater monoamine oxidase a binding in perimenopausal age as measured with carbon 11-labeled harmine positron emission tomography. JAMA Psych 71(8):873–879. CrossRefGoogle Scholar

Copyright information

© World Molecular Imaging Society 2018

Authors and Affiliations

  1. 1.Department of PsychiatryColumbia UniversityNew YorkUSA
  2. 2.Molecular Imaging and Neuropathology DivisionNew York State Psychiatric InstituteNew YorkUSA
  3. 3.Now at Department of PsychiatryStony Brook UniversityStony BrookUSA
  4. 4.Department of Electrical and Computer EngineeringStony Brook UniversityStony BrookUSA
  5. 5.Department of RadiologyColumbia UniversityNew YorkUSA

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